GI Flashcards
(185 cards)
1
Q
what is gord?
A
gastro oesophageal reflux disease
usually caused by weakening/ relaxation in lower oesophageal sphincter
acid from stomach leaks up into esophagus, causing symptoms (heartburn, acid reflux, bad breath…)
2
Q
what are the risk factors of gord?
A
- Smoking
- Alcohol
- Coffee
- Chocolate
- Fatty Foods
- Being Overweight
- Stress
- Medicines (calcium channel blockers, nitrates, NSAIDs etc)
- Tight clothing
- Pregnancy
3
Q
GORD lifestyle advice?
A
- Lose weight if overweight
- Eating small, frequent meals rather than large meals
- Eat several hours before bedtime
- Cut down on tea/coffee/cola/alcohol
- Avoid triggers, e.g. rich/spicy/fatty foods
- If symptoms worse when lying down, raise head of bed (do not prop up
head with pillows) - Avoid tight waistbands and belts, or tight clothing
- Stop smoking
4
Q
GORD OTC management
A
Antacid: Pepto-Bismol®, Rennie®
* Alignate: Gaviscon Advance®
* Dual Product: Gaviscon Dual Action®, Peptac®
PPI or H2 receptor antagonists
5
Q
GORD red flags needing referal
A
- Patients over 55 years with new onset symptoms
- Patients over 55 years with unexplained dyspepsia that hasn’t responded to
2 weeks of treatment - Patients who have continuously taken remedies for 4 weeks (risk of
rebound indigestion) - Pregnant or breastfeeding
- Not responded to OTC treatment
- Red flag symptoms:
- Unintentional weight loss
- Epigastric mass
- Stomach pain, pain/difficulty when swallowing
- Persistent vomiting
- Jaundice
- Signs suggestive of GI bleed
6
Q
GORD POM management
A
- Once confident patient has GORD and no other sinister condition, can offer
full dose PPI for 4-8 weeks
7
Q
what are peptic ulcers?
A
sores that develop in lining of stomach and intestines
gastric ulcer= in stomach
duodenal ulcer= in duodenum
8
Q
signs of peptoc ulcers
A
- Burning or gnawing pain in centre of abdomen
- Indigestion
- Heartburn
- Nausea and vomiting
- Pain can last minutes to hours, and can come and go for several days, weeks or
months
9
Q
peptic ulcers are usually a result of ?
A
helicobacter pylori infection
taking non-steroidal inflammatories (nsaids)
10
Q
complications of peptic ulcers
A
bleeding at site of ulcer
stomach perforation
gastric obstruction
11
Q
diagnosis of peptic ulcers
A
- Take a full history
- Especially to identify NSAID use
- Signs and symptoms
- Physical abdo exam
- Feel for mass, listen for bowel sounds, tap abdomen to check for tenderness or pain
- Urea breath test
- To identify H. pylori infection
12
Q
peptic ulcer POM management
A
due to NSAIDs= stop NSAIDs, use PPI or H2RA therapy for 8 weeks
due to H.pylori= offer H.pylori eradication course
due to NSAIDs and H.pylori= full dose PPI or H2RA therapy for 8 weeks to help ulcer heal first then eradication course
if not due to nsaids or h.pylori= full dose ppi or H2RA for 4-8 weeks
13
Q
what is H.pylori?
A
Helicobacter pylori is a Gram negative bacteria found in the stomach
14
Q
H pylori risk factors
A
- Transmission is through direct contact with saliva, vomit or stool of infected
person, or via contaminated food or water - Living in crowded conditions
- Living without a reliable source of clean water
- Living with someone who has H. pylori infection
common in developing countries
15
Q
complications of h.pylori infection
A
peptic ulcers
gastricitis
stomach cancer
16
Q
H.pylori diagnosis
A
Carbon-13 urea breath test
* Drink liquid containing urea
* If H. pylori present, will break down urea into carbon dioxide
* Patient breathes into bag, which is sent to lab for testing
* If breath sample has higher than normal levels of CO2 , test is positive for H. pylori
infection
* False negatives may occur if test is within 2 weeks of PPI use or 4 weeks of antibiotic
use
17
Q
management of h.pylori infection
A
(no pen all)amoxicillin–> clarithromycin –> any PPI–> PPI+ bismuth subsalicylate+ any 2 abx
(pen all) clarythromycin–> metronidazole–> PPI –> PPI+ bismuth subsalicylate+ rifabutin
18
Q
what are the 2 was of administering tablets
A
pop bottle method
lean forward method
19
Q
what do tablets allow for?
A
ease of administration
accurate dosage
chamical and physical stabiloty
low cost of manufacturing, packaging and shipping
different to tamper with
20
Q
what is comprwssion?
A
reduction in bulk volume, removal of void and bringing particles closer
21
Q
what is consolidation?
A
increased mechanical strength to interparticulate interaction
22
Q
tablet problem?
A
capping and laminating
chipping and cracking
sticking and picking
filming and binding
mottling
23
Q
capping and laminating
A
the upper segment of the tablet seperates from the main portion of the tablet
the seperation of the tablet into two or more distinct layers
24
Q
chipping
A
Breaking of tablet edges as the
tablet leaves the press or during
subsequent handling and coating
operations
25
cracking
Small, fine cracks observed on the
upper and lower central surface of
tablets, or very rarely on the side
walls
26
sticking
Improperly dried or lubricated
granulations causing the tablet
surface to stick to the punch faces
27
picking
Small portions of the
powders/granules stick to the
punch face and grow with each
revolution of the press, picking out
a cavity on the tablet face
28
filming
Due to excess moisture in the
granulation, high humidity, high
temperature or loss of highly
polished punch faces due to wear
29
binding
With excessive binding the tablet
sides are cracked and it may
crumble apart
30
mottling
Unequal distribution of colour with light or dark spots standing out in an otherwise uniform surface
31
coarse sucrose characterisation
tend to be affected more by gravitational forces
32
fine sucrose characterisation
greater surface area possessing attractive forces
33
factors that affect the flowabiloty of the powder
* Particle size and their
distribution
* Particle shape
* Particle interaction forces
(including friction and
electrostatic interactions)
* Environmental factors such as
humidity and temperature
34
factors that could affect tablet hardness
formulation variables
tableting process
storage conditions
35
a weak tablet could be due to
poor tablet design
insufficient binder
over-lubrication
low moisture content
36
what are the digestive phases?
cephalic phase
gastric phase
intestinal phase
37
cephalic phase
anticipatory mechanisms
38
gastric phase
gastric secretions and motility
39
intestinal phase
intestinal secretions and motility
40
4 layers of the gi tract
mucosa
submucosa
muscalaris extera
41
mucosa
epithelial membrane
secretes mucous, digestive enzymes and horomones
absorbs nutrients
protects from disease
epithelial lining
lamina propria
muscalaris mucosae
42
submucosa
moderately dense CT with blood, autonomic nerves an d sometimes also glands, lymoh vessels and lymph follicles
regultaes gut brain action
43
muscalaris externa
intrinsic pacemaker cells regulate smooth muscle contractions
responsible for peristalsis and segmentation
circular layer and longitudinal layer
sphincters (sometimes go thicker to act as valves)
44
serosa (adventicia)
serosa=visceral peritoneum
advenicia= oesophagus has an outer covering of fibrous connective tissues
45
intrinsic nerve plexus (gut brain)
myenteric nerve plexuses
submucosal nerve plexus
46
the gut brain axis
bidirectioal commun ication between the central and the enteric nervous system, linking emotional and conitive centres of the brain with the peripheral intestinal functions
47
peristalsis motility
circular and longitudinal muscles
48
what do we release from the stomach
hydrochloric acid
49
cajal cells in the myenteric plexus
generate rhythm
50
nerve supply of gi tract
external stimuli= central nervous system and extrinsic autonomic nerves
internal stimuli (GI tract)= chemoreceptors, osmoreceptors or mechanoreceptors. local nerve plexus. effectors (smooth muscle or glands)
response= change in contractile or secretery activity
51
reflex
extrinsuc= long + external
intrinsic= short+ internal/ local
52
parasympathetic division to control gastric emptying
increase secretion and motility
release ACh= mucous cells --> mucus
chief cells--> pepsinogen
parietal cells --> HCL
G cells --> gastrin (leave stomach)
53
sympathetic division to control gastric emptying
decrease of secretion and motlity
release adrenaline= mucous cells do not go to mucus
chief cells do not go to pepsinogen
parietel cells do not turn into HCl
G cells do not turn into gastrin
54
gastrin
stimulates t cells to produce hydrocloric acid
this is inhibited by histamine, somatostatin...
55
saliva
can be excreted by intrinsic or extrinsic glands
made of = amylase
mucin
water and protective elements (defensin, IgA, lysozyme)
56
stages of swallowing
buccal phase
pharyngo-oesophageal phase
pharyngo-oesophaegeal phase
peristalsis
sphincter opening
57
types of cells in the stomach
mucus cells
parietal cells
chief cells
enteroendocrine cells
58
chief cells release
pepsinogen (precursor for pepsin which is used for protein digestion)
59
enteroendocrine cells release
gastrin (g cells) pyloric atrium, histamine, endorphins, serotonin, cholecystokinin and somatostatin
60
ECL cells
produce histamine
61
dyspepsi
a group of symptoms that alert doctors to consider disease of the upper GI tract, and states that dyspepsia itself is not a diagnosis
1. upper abdominal pain or discomfort
2. heart burn
3. gastric reflux
4. nausea or vomiting
62
pharmacological treatments of dyspepsia
antacids
mucosal strengtheners
regulation of acid secretion (ppi)
H pylori eradication regimes
63
mechanism of action for ppi
bind covalently to cysteine residues via disulphide bridges on the alpha subunit of the H+/ K+ ATPase pump, inhibiting gastric acid secretion for up to 36 hours. this is antisecretory effect is dose-related and leads to the inhibition of both basal and stimulated acid secretion, regardless of the stimulus
PPIs are pro drugs
sulfenamide binds covalently to exposed cysteine residues of the H+/K+ ATpase pump
pKa ranges from 3.8 to 5.0
metabolised by CYP2c19
omeprazole is an inhibitor of CYP2C9
64
gastroparesis
delayed gastric emptying in the absense of a mechanical obstruction
condition associated=
diabetes mellitus
hypothyrodism
neurological conditions
viral infections
autoimmune attack
iatrogenic causes=
vagal nerve damage during surgery
opioid
alpha 2 adrenic agonists
tricyclic antidepressants
anticholinergics
treatment is for dietary modifictions and avoiding medications that stop gastric emptying
65
what are promotility agents
prokinetic agents refer to a class of drugs that promote the passage of ingested material in the GI
important considerations are is the simple stimulation of gut motility a valid target
target disorders are poorly defined
non selectove drugs will have side effects
66
how do promotility agents work
increase wave like contractions in the oesophagus
increase contractions in the stomach
promote emptying of stomach contents
increase wave like contractions in the intestine
stimulating excitatory chemical messengers
suppressing inhibitory meurotransmitters like dopamine and serotonin
there are 4 types of prokinetic drugs
cholinergc agonists
dopamine antagonist
serotonergic agonists
macrolides
67
dopamine antagonists
block the effect of dopamine in the CNS ans at the chemoreceptor zone
stimulate peristalsis by releasing acetylcholine
MOA= dopamine d2 antagonist
68
dopaminergic regulation of gastrointestinal motility and sites of action of metoclopramide and domperidone
metocloperamide inhibit 5 ht3 going to the myenteric neuron, stops d2 from releasing ach, actovates ach with 5 HT4. the ach then activates the m3 receptor on muscle cells in order to contract
domperidone inhibits d2 to release ah and stops it from acting on the beta 2 receptor in order to contract (activation causes relaxation of muscle cells)
69
seretonergic agonists
mild to moderate gastropresis
serious cardiac risk (doubt to prescribe)
reduce oesophageal acid exposure and promote gastric emptying
70
motilides
(erythromycin)
enhance peristalsis by acting on motolin receptors or by releasing motolin
71
colon
convert chyme into faeces for excretion
lacks vili and has many crypts of lieberkuhn
crypts consist of simple short glands lined by mucus secreting goblet enzymes
the epithelial cells contain almost no digestive enzymes
high capability of absorption of sodium, cl and water
the outer longitudinal muscle layer is modified to form three longitudinal bands, called tenia coli visible on the outer surface
wall is sacculated and forms haustra
72
diarrhoea
abnormal passing of loose or liquid stools, with increased frequecy, increased volume or both
acute= under 14 days
red flag symptoms are weight loss, rectal bleeding, persistant diarrhoea, systemic illness antibiotic or recent hospital treatment, foreign travel
73
diarrhoea treatment
prevention or reversal of fluid and electrolyte depletion and the management of dehydration when it is present
ORT (oral rehydration therapy)
refer if dehydration is severe
antimotility drug loperamide (rapid control)
codeine phosphate
74
constipation
infrequent stools, difficult stool passage or seemingly incomplete defecation
red flag symptoms are over 50 yo, anaemia, abdominal pain, weight loss, blood in stools
75
constipation treatment
increase in dietary fibe, adequate fluid and excersise
laxatives (bulk-forming laxatives, stimulant laxatives, faecal softeners, osmotic laxatives)
Where dietary measures are ineffective:
* Start with a bulk-forming laxative, ensuring
adequate fluid intake.
* If stools remain hard, add or switch to an
osmotic laxative.
* If stools are soft but difficult to pass/inadequate emptying, a stimulant laxative should be added
76
chronic constipation treatment
Start with a bulk-forming laxative, whilst ensuring good hydration.
* If stools remain hard, add or change to an osmotic laxative e.g. a
macrogol. Lactulose is an alternative if macrogols are not
effective, or not tolerated.
* If the response is inadequate, a stimulant laxative can be added.
* The dose of laxative should be adjusted gradually to produce
one or two soft, formed stools per day.
* If at least two laxatives (from different classes) have been tried at
the MDD for at least 6 months, the use of prucalopride (in women
only) should be considered (review after 4 weeks
77
constipation in pregnancy and breast feeding
Pregnancy
1. Diet
2. Fibre supplements in the form of bran or wheat
3. A bulk-forming laxative is the first choice during pregnancy if fibre supplements
fail.
4. An osmotic laxative, such as lactulose, can also be used.
5. Bisacodyl or senna may be suitable if a stimulant effect is necessary but use of
senna should be avoided near term or if there is a history of unstable pregnancy.
6. Docusate sodium and glycerol suppositories can also be used.
Breastfeeding
* A bulk-forming laxative is the first choice, if dietary measures fail.
* Lactulose or a macrogol may be used if stools remain hard.
* As an alternative, a short course of a stimulant laxative such as bisacodyl or senna
can be considered
78
cholestasis
Impairment of bile formation and/or bile flow, which may clinically present with fatigue, pruritus, dark urine, pale stools, jaundice and signs of fat soluble vitamin deficiencies
79
treatment f cholestatic pruritus
* Colestyramine is the drug of choice.
* It is an anion-exchange resin that is NOT
absorbed from the GIT.
* It relieves pruritus by forming an insoluble
complex in the intestine with bile acids
* The reduction of serum bile acid levels
reduces excess deposition in the dermal
tissue with a resultant decrease in pruritus
80
gallstones
Gallstones occur when hard mineral or fatty deposits form in the gallbladder.
* Gallstone disease = presence of one or more stones in the gallbladder.
* Usually asymptomatic.
* When the stones irritate the gallbladder or block part of the biliary system, the patient can experience symptoms such as pain, or infection and inflammation that if left untreated, can lead to severe complications such as biliary colic, acute cholecystitis, pancreatitis, and obstructive jaundice
81
treatment of gall stones
surgical removal by laparoscopic cholecystectomy
analgesics to control pain (or NSAIDs)
intramuscular diclofenac sodium for pain
or morpheine
82
obesisty
BMI more than 30kg/m2
men= waist more than 94 cm
women= waist more than 80 cm
83
anal fissure
An anal fissure is a tear or ulcer in the lining of the anal canal, immediately within the anal margin.
* Clinical features include bleeding and persistent pain on defecation, and a linear split in the anal mucosa
84
treatment of anal fissure
acute=
bulk forming laatives
osmotic laxatives
short gterm use of local anasthetics
chronic(more than 6 weeks)=
GTN rectal ointment
85
haemorrhoids
Haemorrhoids, or piles, are abnormal swellings of the vascular mucosal anal cushions around the anus.
* Internal haemorrhoids arise above the dentate line and are usually painless unless they become strangulated.
* External haemorrhoids originate below the
dentate line and can be itchy or painful.
86
treatment of haemorrhoids
bulk forming laxatives if consitaption is there
simple analgesics for pain
opioids and nsaids to be avaoided as these can cause constipation and rectal bleeding
topical corticosteroids for occasional short term use
87
reduced exocrine secretions
Reduced secretion of pancreatic enzymes into the duodenum.
* Clinical manifestations: maldigestion and malnutrition, associated with low circulating levels of micronutrients, fat-soluble vitamins and lipoproteins. Patients also present with GI symptoms such as diarrhoea, abdominal cramps and steatorrhoea
88
treatment of reduced exocrine secretions
pancreatic enzyme replacement therapy with pancreatin (contains three main groups of digestive enzymes l;ipase, amylase and protease)
taken with food (not hot food)
alcohol should be avoided completely
89
genetic variability
Individuals have unique genetic profiles that can affect how they metabolise and respond to drugs. These differences are due to variations in genes that encode for drug-metabolising enzymes (DME), drug transporters, drug receptors and targets
90
drug metabolism
Genes can influence the levels and activity of DME. For instance, some
people have genetic variants that make them metabolise drugs more quickly or slowly than
others
91
drug targets
Genetic variations can also affect drug targets such as receptors or proteins,
altering the drug’s effectiveness
92
phase 1 metabolism
Phase 1 reactions often introduce a reactive
group, such as hydroxyl, into the molecule, a
process known as ‘functionalisation’. This
group then serves as the point of attack for the
conjugating system to attach a substituent
such as glucuronide
Phase 1 reactions (e.g. oxidation, reduction or
hydrolysis) are catabolic, and the products are often more chemically reactive and hence, paradoxically, sometimes more toxic or
carcinogenic than the parent drug
93
key genetic factors that influence the treatment of various gastrointestinal disorders
IBS= serotonin transporter, cyp2c19 and cyp2d6
IBD= TPMT, NOD2/CARD15
GERD and peptic ulcers= cyp2c19
94
ppi moa
inhibit H-K-ATPase, the final step of gastric acid
secretion by parietal cell
pro drug
metabolised by cyp2c19
95
coeliac disease
chronic immune mediated systemic disorder in genetically pre-disposed people triggered by exposure to dietary gluten
96
management of coeliac disease
gluten free diet
monthly units allocations oer patient
GF items given unit value
97
diverticular disease and diverticulitis
sac like protrusions in muscular wall of colon
98
management of diverticulosis
Advise that condition is asymptomatic and no
treatment needed
* Signpost to advice & info.
* Advice on healthy balanced diet
* Advice on fluid intake
* Advice on exercise & weight loss if overweight/obese
99
management of diverticular disease
* Urgent admission if significant rectal bleeding
* Advice on avoiding use of NSAIDs and Opioids
* Advice on diet, lifestyle, exercise, weight loss,
smoking cessation, fluids
* Advice on when to seek urgent medical attention
* Consider bulk forming laxative, paracetamol,
antispasmodic
100
management of diverticulitis
Admission if complicated, dehydrated, no oral
tolerance, aged over 65, co- morbidity or
immunosuppressed
* Oral antibiotic
* Co-amoxiclav
* Cefalexin + Metronidazole or Trimethoprim + Metronidazole in penicillin allergy
101
drug treatment of N and V
metoclopramide
domperidone
antihistamines
hyoscine hydrobromide
dexamethasone
5HT3-receptor antagonists
(in pregnancy offer self-care, 1st line cyclizine)
102
IBD
Collective term used to describe 2 conditions that cause inflammation of the GI tract:
Ulcerative Colitis (UC) – Mostly affects colon and rectum
Crohn’s Disease (CD) – can affect anywhere in GI tract
103
extra-intestinal symptoms in IBD
related to disease activity
* Pauci-articular arthritis
* Erythema nodosum
* Mouth Ulcers
* Episcleritis
* Osteopenia, Osteoporosis, Osteomalacia
* VTE
not related to disease activity
* Axial arthritis
* Polyarticular arthritis
* Pyoderma gangrenosum
* Psoriasis
* Uveitis
* Hepatitis
* Liver Cirrhosis
* Gallstones
104
ulcerative colitis
chronic, relapsing-remitting, non-infectious inflammatory disease of the gastrointestinal tract
bloody diarrhoea/ rectal bleeding for more than 6 weeks
unexplained weight loss
105
toxic megacolon
* Potential life-threatening complication
* Dilatation of the colon with increasing abdo. pain & systemic symptoms
* Colonectomy possibly required
* Abso x-ray shows dilatation of transverse colon
* Causes - relapse, infection, hypokalaemia, hypomagnesaemia, anti-diarrhoeal medication
106
treatment of ulcerative colitis
Corticosteroids
Aminosalicylates
Azathioprine & Mercaptopurine
Methotrexate (MTX) – Poor evidence base for use
Ciclosporin
Biologics
Surgery – Ileostomy, colostomy, stoma
107
thiopurine methyltransferase
* Enzyme that metabolises thiopurine drugs
* Patients with reduced levels are at increased risk of myelosuppression
* TMPT test/screen must be conducted before treatment
* Reduced or low TPMT activity patients must be treated or remain under
specialist supervision
* Reference ranges
Normal: 68 – 150 mU/L
Low: 20 – 67 mU/L
High: >150 mU/L
108
acute severe ulcerative colitis
Step 1
* Hospital admission
* MDT Care – Gastroenterologist, colorectal surgeon, IBD Nurse, Stoma Nurse, Paediatric
Gastroenterologist if child, Obs. & Gynae. if pt. pregnant
* IV corticosteroid & assess for surgery
* IV ciclosporin if corticosteroid not tolerated, contraindicated or declined
Step 2
* Add IV ciclosporin to IV corticosteroid or consider surgery if:
Little/no improvement within 72hrs of IV corticosteroids
Symptoms worsening
* Infliximab if ciclosporin contraindicated or not appropriate – Risk v. Benefit
109
crohns disease
chronic, relapsing-remitting, non-infectious inflammatory disease of the gastrointestinal
tract
110
treatment of CD
Glucocorticoids & Budesonide
Aminosalicylates
Azathioprine & Mercaptopurine
Methotrexate (MTX) – Poor evidence base for use in UC
Ciclosporin
Biologics
Surgery – Ileostomy, colostomy, stoma
111
antacids
* Used to treat heartburn / indigestion /
upset stomach
* Works by neutralising stomach acid
* Most commonly contain magnesium
hydroxide or aluminium hydroxide (or
a combination of both)
112
H2 receptor antagonists
* Used to treat acid-peptic disease
(duodenal ulcers, gastric ulcers,
gastroesophageal reflux disease,
common heartburn)
* Block the action of histamine at the
histamine H2 receptors of the parietal
cells in the stomach
113
promotility agents
* Used to treat conditions with slow movement of matter through the digestive system
(gastroparesis, constipation)
* Two main mechanisms of action:
Enhancing the effect of acetylcholine (smooth muscle
contraction)
Blocking the effect of an inhibitory neurotransmitter, e.g.
dopamine
114
laxatives
Used to treat constipation and
conditions with limited movement
through the digestive system
* Accelerate fecal passage or decrease
fecal consistency
* Mechanisms of action:
Increase fluid retention by hydrophilic or osmotic
mechanisms
Decrease absorption of fluid by manipulation of
electrolyte transport
Stimulation of propulsive contractions / inhibition
of non-propulsive contractions
115
antidiarrheal drugs
antimotility agents
anticholinergic agents
116
ppis
* Used primarily for gastric ulcer treatment, e.g. omeprazole
* Racemic prodrug (omeprazole) converted to active metabolite (cyclic sulfenamide) in parietal cells
* Inhibits gastric acid secretion by inhibiting H+, K+ -ATPase
* Mechanism of action involves a disulphide bond with the enzyme
* Proton pumps regulate the flow of cations into
and out of the cell, to maintain cell functions
* If protons are not excreted efficiently, the cell
process could slow down (equilibrium, Le
Chatelier’s Principle)
* Ion channels control the flow of other ions into
and out of the cell – work via ion gradient
117
activation of ppis
* Protonation takes place on the
benzimidazole ring
* Nitrogen of the pyridine ring then acts as a
nucleophile – uses its lone pair of electrons
to forma a bond with the electron deficient
2-carbon of the benzimidazole ring
* The spiro structure is formed – aromatic
character of the imidazole portion of the
ring is lost
* The ring wants to re-aromatise
* The lone pair of e- from the nitrogen
reform the double bond and cleave the S-C
bond, forming sulfenic acid
* Sulfenic acids are highly reactive – rapid
reaction of an intramolecular attack by the
NH group of the benzimidazole on the
sulfenic acid, displacing the hydroxyl group
* The cationic, tetracyclic, pyridinium
sulfenamide is formed and is an irreversible
enzyme inhibitor
* It forms a covalent bond to an accessible
cysteine residue on the proton pump
* Cys-813, Cys-821, Cys-892 all have the
potential to be attacked, depending on the
drug
* Omeprazole prefers Cys-813 and Cys-892,
pantoprazole only reacts with Cys-813.
118
metabolism of PPIs
* Metabolised by cytochrome P450 enzymes
* Primarily S-mephenytoin hydroxylase (CYP2C19)
and nifedipine hydroxylase (CYP3A4)
* 3% of white European people are slow metabolisers
of PPIs
* Pantoprazole is also metabolised by
sulfotransferase, whereas omeprazole and
lansoprazole are not
119
immunosuppresive drugs
* Thiopurines are the main class of
drugs used to maintain remission if
corticosteroids are needed
following 2 or more exacerbations
in a 12-month period
* Should only be used if
aminosalicylates are not effective
* Methotrexate is the second line
option after thiopurines
* Thiopurines are known to increase
the risk of non-melanoma skin
cancer
120
antispasmodics
antimuscarinics
smooth muscle relaxants
121
aminosalicylates
* Specialist drug treatment for ulcerative colitis
* Also considered for mild-moderate proctitis
and proctosigmoiditis
* Usually prescribed topically (suppository or
enema)
* Prescribed for oral use if remission not
achieved in 4 weeks
* 5-aminosalicylic acid (5-ASA) activates a class
of nuclear receptors involved in the control of
inflammation, cell proliferation, apoptosis and
metabolic function (peroxisome proliferator-
activated receptors)
* The receptors are highly expressed in colon
epithelial cells
* Oral administration of 5-ASA tablets / capsules
is ineffective as it is absorbed in the small
bowel due to slow transit time so effective
concentrations do not make it to the distal gut
122
mesentric arteries?
mesentric arteries needs to be connected to the liver hepatic portal vein because the mesentric material needs to be drained into the liver because the liver processed them and then sends them out
123
parasympathetic GI
excitatory
124
sympathetic GI
inhibitory
125
mastication
chopping and grinding food in the mouth, also with enzymes from saluvary glands, also includes water to create bolus and lysozyme as an antibacterial
126
gastric mucosa layers
the gastric muscosa has layers of mucus surface layer(protective layer),
mucus neck cell (buffers gastric acid to prevent damage to the epithelium),
parietal cells ((gastric acid)activates pepsin), (intrinsic factor)complexes with vitamin b12 to permit absorption),
enterochromaffinlike cells (stimulates gastric acid secretion),
chief cells ((pepsinogen) digests protein, (gastric lipase) digests fats)
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acid in the stomach lumen causes a release and activation of ...
pepsin(digest protein),
somatostatin release from D cells, denatures protein, kill bacteria, inactivates salivary amylase
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fat breakdown in the stomach
fat breakdown in the stomach is by gastric lipase is from TGs to DGs and free fatty acids
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small intestine structures
the small intestine is comprised of the structers of duodenum (mixing of chyme and secretions from gall bladder and pancreas ducts),
jejunum (further segmentation and secretions of acids and enzymes),
ileum (absorption of left over digested carbs, fats and proteins)
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intestinal secretions
mucus(protects duodenum),
sucrase, lactase, maltase and amylase to digest carbohydrates and are absorbed via glucose transporter
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horomones of stomach and gallbladder
cholecystokinin (stimulate gallbladder contractions),
secretin (stimulate bicarbonate secretion and inhibit gastric emptying),
gastruc inhibitiry peptide (inhibits gastric emptying),
glucagon like peptide 1 (inhibit gastric emptying and secretions)
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bile and bile salts
the gall bladder is a small pouch like organ found underneath the liver for storage and concentrate bile and it is passed from the liver into the gallbladder through a series of channels known as bile ducts
bile is a nonenzymatuc solution secreted from hepatocutes (liver cells)
bile salts act as a deterant to solubilise the fat and move them forward in the small intestine
nile salts coat fat droplets, pancreatic lipase breaks them into monoglycerides, MGLs breakdown into free fatty acids and cholestrol diffuses through enterocytes (cells of the small intestine), absorbed fat, cholestrol and proteins form chylomicrons, these are removed through the lymphatic system
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peristalisis
contraction and relaxation of circular and longitudinal muscles
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immune functions of the GI tract
lead to the actiavtion of M cells which leads to M cells present antigen to immune cells, immune cells release cytokines and activate immune and inflammatory cascades, inflammatory cascade increase the secretion of Cl-, fluid and mucus to flush the invaders from the GI tract
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startch or glycogen metabolism by amylase
glucose+ glucose= maltose
glucose+ fructose= sucrose
glucose+ galactose= lactose
these are then metabolised by maltase, sucrase and lactase to form glucose, fructose or galctose
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protein metabolism
all proteins are broken down into di/tri peptides and absorbed in the small intestine
proteins made of peptides and acid aminos go through metabolism by endopeptidases to form smaller peptides, these then go through metabolism by exopeptidases to form di/tri peptides, amino acids
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advantages of GI absorption
advantages of gi absorption are large surface area, range of pH environments, richly vascularised, long tract and long dwell time, some active transprt, small intestine is a major site for drug absorption
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defences of GI infections
mucus secretion, secretory IgA, persistalsis, fluids with antimicrobial prop, gut assosiated lymphoid tissues
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structural function of flora
enhance epithelial barrier
protection where it has colonisation resistance, competitive exclusion of p[athogens, immunity activation, and antimicrobial secretion directly or indirectly (by the induced intestinal epithelium)
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metabolic functions of the flora
synthesis of the essential b group vitamins (folic acid) and vitamin K, dietary fibre fermentation into short chain fatty acids, absorption facilitation of dietary minerals, bile acids biotransformation and metabolisisng sterols and xenobiotics
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why do helathy individuals have a high colonisation resistance?
commensal bacteria are dominanat and outnumber the pathogens preventing them to colonise the gut
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gastroenteritis
gastroenteritis is a GI infection, resulting in inflammation of stomach and intestinal lining
gastroenteritis symps of diarrheal vomitting and abdominal pain
the cause of this could be from many bacteria (campylobacter jejuni, salmonella, shigella, clostridium difficile, staphylococccus aureus), viruses (noroviruses) and parasites (giardia lamblia)
sources of these are from food poisoning or food intoxication
in bacterial gastroenteritis antibiotics are generally not needed (incase severe)
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exotoxins
exotoxins are produced inside mostly gram positive bacteria as part of their growth and metabolism, soluble and heat labile proetins, released into host tissue and can travel in bodily fluids, produced by gram + and -
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enterotoxins
enterotoxins affect lining and function of gastrointestinal tract causing nausea, vomiting and or diarrhea. (AB enerotoxins (vibrio enterotoxin))
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pore forming toxins
pore-forming toxins which insert pores inside the cell membrane and the cell host releases the internal contenet outside causing lysis
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superantigen toxins
superantigen toxins where immune system overstimulation to produce cytokines and pro-inflammatory molecules results in failure of multiple host organs allowung time for the membrane to disseminate
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endotoxins
endotoxins are part of the outer portion of the cell wall of gram negative bacteria, liberated when the bacteria die and the cell wall breaks apart
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clostridium difficile
clostridium difficile is an opportunistic pathogen, it is a gram positive, anaerobic, spore-forming bacillus, germinate in the intestine when microbiota is altered (colonising the area)
clostridium difficile produce an enterotoxin (toxin A) and cytotoxin (toxin B)
toxin A primarily distrupts the cytoskeletal structure and the tight junctions of epithelial intestinal vells causing cell rounding
toxin B induce cell death
c.difficile pathogenesis is transmitted by the feca-oral route, once ingested it can germinate to vegative cells upon exposure to bile acids, then colonise, produce toxin a and b, which disrupt epithelial lining, release inflammatory mediators and cause inflammatory changes
diagnosis of c. difficile is through colonoscopy, toxin a and b detection, PCR based analysis
treatment is vancomycin 125mg qds (first line), fidaxomicin 200mg bd for 10 days (second line)
treatment in patients with life threatenung C.difficile infection is urgent referal to hospital --> oral vancomycin with intravenous metronidazole
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GORD
gastro oesophageal reflux disease
heartburn acid refluc bad breath bloating nausea vomiting
triggers= smoking, alc, coffee, chocolate, fatty foods, spicy, overweight, stress, tight clothing, pregnancy
diagnosis made solely on symp
take a full drug history (calcium antagonists, nitrates, NSAIDs, theophylines, bisphosphorates, corticosteroids)
lifestyle advice: lose weight, eating small, eat several hours before bed, prop up with pillows, acoid triggers, stop smoking
OTC management: anatacids (pepto bismol, rennie), alginate (gaviscon), dual product (gaviscon dual, peptidac)
OTC management (longer acting): PPIs or H2 receptor antagonists (guardium)
GORD red flags: over 55 with onset symp, over 55 with symps for more tha 2 weeks with treatment, taken remedies for 4 weeks, preg or breast, not responding to treat, unintentional weight loss, epigastric gas, stomach pain, jaundice, GI bleed signs(dark stool), difficulty when swallowing
POM management:full dose PPIs for 4-8 weeks (omeprazole 20mg, lansoprazole 30mg) or H2 receptor anatgonists if patients cannot tolerate PPIs (ranitidine)
PPI issues are risk of development of lupus, risk of fractures(in elderly), GI infections (C.diff), masking gastric cancer, interactions(with clop), side effects (abdo pain, nausea and vommiting)
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peptic ulcer
spores that develop in lining of the stomach(gastric) and intestines (duodenum)
symp: burning or gnawing pain in abdomen, indigestion, heartburn, nausea and vom, pain can last minutes to hour
risk factors: over 60, male, when protective lining of stomach is damaged
causes: H.pylori infection(bacteria damages mucous coating in stomach, HCl can reach linibg and the bacteria can irritata the lining causing the ulcer), taking NSAIDs (block COX-1 enzymes that is used in GI mucosal protection, therefore protective lining becomes vulnerable to stomach acid causing an ulcer)
complications: bleeding at site of ulcer, stomach perforation, gastric obstruction
diagnosis: take a full history (nsaids), physical abdo exam, urea breath test(h.pylori), might refer for endoscopy
POM management:due to NSAIDs= stop NSAIDs--> full dose PPI or H2RA therapy for 8 weeks
due to H.Pylori= H.pylori eradication course
due to NSAIDs and H.Pylori= full dose PPI or H2RA therapy for 8 weeks to help ulcer heal first--> H.pylori eradication course
not due to NSAIDs or H.pylori= full dose PPI for 4-8 weeks
monitoring: PPI as a course, manage pain without NSAIDs, symp comes back--> low dose PPI
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H. pylori infection
helicobacter pylori is a gram negative bacteria found in the stomach
risk factor: transmission through direct contact with saliva, vomit or stool of infected person, living in crowded conditions, without a clean water supply, living with someone infected
complications: peptic ulcers, gastritis, stomach cancer
diagnosis: carbon 13 urea test (drink liquid containig urea, if H.pylori is present it will break down the urea into carbon dioxide, if breath test comes back with more carbon dioxide than normal then it is positive for H.pylori infection), stool or blood test
management: triple therapy (antibiotic 1+ 2+ PPI)(duration of 7 days)
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differance between sugar and film coating
film coating retains contour of original core and not as shiny
sugar coating is rounded with a high degree of polish and also has a higher weight increase of 30-50%
sugar coating is multistages whilst film coating is a single stage
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suppositories manufacture
apply lubricant --> add molten base and drug--> allow to solidify
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suppository problems
bubbles, unevenly dispersed, not enough lubricant leads to broken in half (not cooled properly)
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pacemaker cells
pacemaker cells are interstitial cells of cajal in the myenteric plexus to generate rhythmic depolarization and repolarization in peristalis and segmentation
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para gastric emptying
in parasympathetic gastric emptying there is a release of ACh, cholenergic fibres and an increase of secretion and motility. these lead to an increase of mucus from mucous cells, pepsinogen from chief cells, HCl from parietel cells and gastrin from G cells
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symp gastric emptying
in sympathetic gastric emptying there is a decrease of secretion and motility there is a release of adrenergic fires and a release of adrenaline. these cause no mucus to be released or pepsinogen or HCl or Gastrin
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gastrin
gastrin stimulates somatostatin, that inhibits HCl release
gastrin also stimulates histamine
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HCl
HCl is used to activate pepsin from pepsinogen
histamine stimulates HCl
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dyspepsia
dyspepsia is a group of symptoms that alert doctors to consider disease(upper abdo pain, heartburn, gastric reflux, nausea or vom)
treat: antacids, mucosal stengtheners, reduction of acid secretions (PPIs, H2RA), H.pylori eradication regimes
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gastroparesis
delayed gastric emptying in the absence of a mechanical obstruction
promotility agents promote the passage of ingested material in the GI by
increase wave like contractions in the eosophagus, increase contractions in the stomach by stimulating exitatory chemical messengers and suppressing inhibitory neurotransmitters like dopamine and serotonin
dopamine antagonists (metoclopramide, domperidone) block the effects of dopamine in the CNS and at the chemoreceptr zone, stimulate paristalsis by releasing acetylcholine
serontonin agonists (cisapride and prucalopride) activte serotonin receptors to release actylcholine
motilides (erythromycin) enhance peristalisus by acting on motilin receptors
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large intestine
primary role of large intestine is to absorb water and vitamins and to convert chyme into faeces
large intestine lacks vili but has many crypts of lieberkuhn
the outer longitudinal layer muscle is modified to form three logintudinal bands called tenia coli visible on the ouuter surface
stimulation of pelvic nerves (need to go) cause persitalsic motility and incresed mucus secretion
control the external sphincter to stop uncontrollable feacal release
no control of internal sphincter
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vomitting
vomiting is caused by GI distress which then act on ECL to release serotonin in response to toxins and bonds to TD 5-ht3 receptors on the vagal nerve, goes up the afferent pathways, then binds to the vomitting center to the dopamine receptor to cause vomiting reflex
vomiting reflex is the pre-ejection phase, retching phase, expulsion phase
anti-emetics are histamine 1 receptor antagonists, 5-HT3 receptor antagonists, dopamine receptor antagionists, musclarinic receptor antagonists
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IBS
in irritable bowel syndrome the serotonin transporter gene and the CYP2C19 genes influence the treatment
in infalmatory bowel disease the TPMT enzyme influenses the treatment
azathioprine (pharmocogenomics): indicated for crohns disease, contraindications with absent TPMT activity cause hypersensitivity, neutropenia and thrombocytopenia
azathioprine is an immunosuppresant for autoimmune disease, it is a pro drug of mercatopurine, that is metabolzed by TPMT
TPMT is thiopurine methyl transferase
measurement of TPMT before treatment
chronic relapsing and often debilitating disorder of gut-brain interaction
symp- change in stool form and/ or frequency, abdominal pain, abdominal bloating
causes: infection , genetic, gi inflammation, diet, physiological
diagnosis: history, abdo pain 6 months+ which is either relieved by defacation or drugs
tests: weight, abdominal palpitations, rectal exam, blood test (FBC), faecal calprotectin
managemnet: dieticians, diet and lifestyle (balanced diet, fibre intake, fluid, weight management)
drug treatments: laxatives
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diarrhea
abnormal passing of loose or liquid stools, with increased frequency, increased volume or both
acute= less than 14 days
symps improve 2-4 days
investigate to discover any red flags
prevention or reversal of fluid and electrolyte depletion
important in infants, frail and elderly (dehydration can be deadly)
treatment: ORT, refer to heosp if dehydration, antimotility drug loperamide HCl (rapid control), codeine phosphate
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constipation
infrequent stools, difficult stool passage, or seemingly incomplete defcation
new onset for over 50 years old patients with symptoms of anaemia, abdo pain, weight loss or blood in stools shows a risk of malignancy
secondary constipation can be caused by a drug
treatment: increase in dietary fibre, fluid intake and excercise, fibre intake increased gradually, laxative (can lead to hypokalaemia), fruit high in sorbitol
laxative: bulk forming laxative(value in small hard stools, onset of action is 72 hours, first line, bran, ispaghula husk, methylcellulose), stimulant laxatives (bisacodyl, senna, sodium picosulfate, increase intestinal motility and often cause abdo pain), faecal softeners (act by decreasing surface tension and increasing penetration of intestinal fluid into the faecal mass, docusate sodium and glycerol enemas containing arachis oil, liquid paraffin), osmotic laxatives (increase amount of water in the large bowel, lactulose, macrogols)
laxative treatment: bulk forming--> osmotic--> stimulant
in preg: fibre and diet --> bulk forming--> osmotic--> stimulant--> suppositories
in child: laxative+ diet+ behaviroral interventions (diet not by itself)
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cholestasis
impairment of bile formation and/or bile flow
symp: fatigue, pruritus, dark urine
treatment: colestyramine (anion exchange renein that is not absorbed)
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gall stones
hard mineral or fatty deposits form in the gall bladder
gallstone disease= presence of more than one stone in gallbladder
treatment (asymptomatic): no treatment
treatment (symptomatic): surgical removal
drug treatment: analgesia to control pain
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obesity
BMI more than 30 kg/m2
waist circ (men more than 94 cm)(women more than 80cm)
treatment= weightloss into maintenance
drug treatment= orlistat 120mg (60mg OTC)
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anal fissure
tear or ulcer in the lining of the anal canal, immediately within the anal margin
aims of treat: pain and promote healing
drug treatment: acute=soft stools (laxatives) --> local anaethstetics
chronic)more than 6 weeks)=GTN ointment
non drug+ surgery
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haemorrhoids
abnormal swellings of the vascular mucosal anal cushions around the anus
internal haems arise above dentare line and are usually painless
external haems originate below the dentate line and can be itchy or painful
aims of teat: reduce symp, and prevent reoccurance
non drug treatment:soft stools by increasing fibre and fluid intake, hygeine
drug treatment: bulk forming laxative, paracetamol, topical combinations of local anaesthetics and antiseptics, topical corticosteroids (short term 7 days after infection)
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reduced exocrine secretion
reduced pancreatic enzymes leads to maldigestion and malnutrition,patient also presents with GI symptoms
aims of treat: relieve GI symptom and achieve normal nutritional status
treatment: pancreatic enzyme replacement therapy with pancreatin(lipase, amylase and protease)(administered with food, not hot food)
give high fat diet
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coeliac disease
diagnosis:hard, suspect if unexplained gi disturbances
caused by heightened immune response to gluten
management: gluten free diet
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diverticulitis
sac like protrusions in muscular wall of colon
diagnosis: difficult as most are asymptomatic, intermittendt abdo pain in lower left quadrant triggered by eating
management: oral antibiotic , diet, admission
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N and V
sensation of unieasiness in the stomach which may or may not lead to vomiting
drug treat: metoclopramide 10mg TDS (post op and chemotherapy induced), domperidone 10mg TDS , antihistamines (post op, paalitive, travel , meniere disease)
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IBD
inflammation in the GI tract
ulcerative colitis and crohns disease
symp: pain, swelling in abdo, recuuring diarrhoea, weight loss, tiredness (symptom fluctuation)
extra-intestinal symp: (more common in CD) pauci-articular arthtitis, erythema nodosum, mouth ulcers, axial arthritis, pyoderma gangrenosum
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ulcerative colitis
chronic, relapsing-remitting, non-infectious inflammatory disease of the GI tract
ulcerative procitis (rectum only)
left sided colitis (splenic flexure)
extensive colitis (whole colon)
studies: colonoscopy, uper intestinal endoscopy, magnetic resonanse enterography
treat: corticosteroids, aminosalucylites (blood count, liver function, renal functions), methotrexate
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crohns disease
chronic replasing-remitting, non-infectious inflammatory disese of the GI tract
inflammation anywhere in the GI tract
diagnosis: pale, finger clubbing, mouth ulcers, abdo pain, parianal pain, anal fissure, malnutrition, malabsorption
treatment: glucocorticoid (1st presentation or 1 exacerbation in 12 months), azathioprine (2 or more exacerbations), biologics (until treatment failure or after 12 months)
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activation of PPIs
activation of PPIs happen as Protonation takes place on the
benzimidazole ring Nitrogen of the pyridine ring then acts as a nucleophile – uses its lone pair of electrons to forma a bond with the electron deficient 2-carbon of the benzimidazole ring The spiro structure is formed – aromatic character of the imidazole portion of the ring is lost The ring wants to re-aromatise The lone pair of e- from the nitrogen
reform the double bond and cleave the S-C bond, forming sulfenic acid Sulfenic acids are highly reactive – rapid reaction of an intramolecular attack by the NH group of the benzimidazole on the sulfenic acid, displacing the hydroxyl group The cationic, tetracyclic, pyridinium
sulfenamide is formed and is an irreversible enzyme inhibitor It forms a covalent bond to an accessible cysteine residue on the proton pump Cys-813, Cys-821, Cys-892 all have the potential to be attacked, depending on the
drug Omeprazole prefers Cys-813 and Cys-892,pantoprazole only reacts with Cys-813.
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protecting group
a chemical modification of a functional grou which allows for chemoselectrivity in a reaction/ synthesis
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what protecting grous must do
react selectively, provide a good yeild, selectively removed, have no additional functionality, no additional stereocentres
182
commonly used protective groups
alcohols, carbonyls and amines
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uses of prodrugs
increase solubilit, improve taste, increase stability, reduce toxicity, modify the time of duration of action, deliver drugs to specific site in the body, aleviate pain when administered by injection
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drug allinances
when some drugs affct the activity of other drugs in a good way
examples of this is: sentry drugs (second drug aministered with the princple drug, usually to inhibit the enzyme metabolizing it), localizong the area of activity, increasing absorption
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excipients
filler= lactulose
binder= PVP, startch , gelatin
disintegrant= startch
lubricant= magnesium stearate
glidant= colloidal silica, talc, cornstartch
